DCI has shown promise as a therapeutic agent to treat insulin resistance and those conditions associated with the disease such as NIDDM. Studies on primate models indicate that 1 gram per day is a reasonable dose upon which to base initial forecasts. There are 14 million diagnosed NIDDM patients in the United States. It is estimated that 20% of the general population is genetically predisposed to insulin resistance and therefore it is expected that daily manufacturing capacities for DCI will need to approach megagram quantities.
DCI can be isolated in kilogram quantities from natural sources. One of these sources is the California sugar pine. It has been shown that a 15 weight percent of pinitol (the 3-0 methyl ether of DCI) can be extracted from the sawdust of this tree's stump. Pinitol can easily be converted to DCI in quantitative yield. With a yield of 1 kg/stump, an estimated 35 million stumps per year will be needed to supply the United States market demand with DCI (this calculation does not incorporate the fact that the stump ideally should be aged 5 years or more). Therefore, it is unlikely that the projected demand of DCI will be satisfied through this source.
DCI is also 40% of the antibiotic kasugamycin and is easily cleaved and purified from the antibiotic. Sources for kasugamycin have yet to prove to be economical. Attempts to produce a viable strain of S. kasugaensis either by natural selection techniques or fermentation process modifications have yet to yield a desirable result.
There have been several reported syntheses of chiroinositol (or its easily converted methyl ether) and they either entail a series of exhaustive protection/deprotection steps or fail to give the pure D-chiro isomer in a reasonable fashion. Martin-Lomas, et. al., reported a synthesis of 1-0-methyl-D-chiroinositol from methyl glucopyranose (compound 1) utilizing the well-known Ferrier rearrangement. This approach required that the glucose molecule be subjected to a 4-step protection sequence leading to compound 2 which when rearranged yielded the key intermediate compound 3. Converting compound 3 to 1-0-methyl-D-chiroinositol involved four synthetic steps. Demethylation, as described above, would require an additional step for a total synthesis of DCI in 10 steps.
Ozaki and coworkers devised an approach to DCI starting from glucuronolactone (a.k.a. glucurone, compound 4). This synthesis involves a total of 17 steps, involving seemingly unnecessary manipulations and utilizes exotic reagents such as titanium tetrachloride which is the key reagent in the sequence shown in entry 2 of FIG. 1. In 1990, Shen and coworkers synthesized DCI from myoinositol by selectively epimerizing the 3-D position of myoinositol as shown in entry 3 of FIG. 1. This was done in 5 steps, however, one of the steps yielded a relatively small amount of product and another step involved a labor intensive separation of diastereomers.
The last two syntheses of DCI (entry 4 of FIG. 1) reported are similar in that the key step is a Pseudomonas putida oxidation of benzene) which generates a meso compound) or chlorobenzene (which generates an optically active compound) to the cyclohexadienediol derivatives 10 and 11. Hudlicky imparted a novel approach to convert 11 to DCI in 4 steps for a total of 5 steps; the final product, however, was contaminated with alloinositol, another of the nine isomers of inositol.